Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect systems and organs throughout the body. The pathogenesis is unknown, but in the numerous cases, it is considered to be an autoimmune rheumatic disease activated by polyclonal B cell in vivo and autoantibodies against autoantigens. Western medicine treatment of SLE currently mainly involves glucocorticoids and cytotoxic drugs or immunosuppressive agents; Even though these methods can prolong a patient's survival, long-term usage or high-dosages of such hormones can cause gastrointestinal bleeding, osteoporosis, infections and other complications, which cause many complications for the treatment. Therefore, it is urgent to study an effective and reliable, minimal side-effect and economical drug treatment, to meet the different needs of patients.
As2O3, commonly called arsenic trioxide, is highly toxic, but is a compound with a wide range of functions. It has a long medical history in China, and has been used for the treatment of psoriasis, syphilis, rheumatism, and certain maladies. As a traditional Chinese medicine, arsenic was first an invention and contribution of great significance in the field of drug development and treatment of leukemia, and was universally acknowledged. In recent years, because As2O3 plays a significant role in acute promyelocytic leukemia treatment, many scholars have conducted in-depth studies on the drug which has demonstrated that As2O3 can treat a broad range of tumors. Not only does it have excellent inhibitory effect on leukemia cells, but it also is effective against many solid tumors, including lung cancer, pancreatic cancer, esophageal cancer, ovarian cancer, stomach cancer, colon cancer and so on.
Many scholars in China and abroad have intensely studied the structure of arsenic through the scope of modern medicine. Studies have shown that arsenic, in a trivalent state, works in vivo. Trivalent arsenic is a complexing agent of thiol (—SH), and can inhibit metabolic?? activity (of what) after interaction with thiol in the interior of enzyme molecule, which induces apoptosis through a number of pathways, demonstrating that As2O3 is very effective against tumors. Wei Yaming etc. (Northwest Military Medical Journal, 2002, 23 (5): 324-326.) reported dual effects of As2O3 on apoptosis and differentiation of leukemia cells. As2O3 is found that lower concentration of As2O3 has no effect on expression of differentiation antigen of NB4 and HL-60 cell lines, and only high concentration of As2O3 treated for more than 72 h could play effects of both apoptosis and differentiation. Meanwhile, mechanism of action of As2O3 on cytokines and immunomodulatory has also caused extensive concerns, some studies: Zhu Xiaochun, etc. (Chinese Journal of Internal Medicine, 2001, 40 (11): (764-765); (Chinese Journal of Rheumatology, 2002, 6 (5):343-346) postulated that As2O3 could control or reduce autoimmune responses by inducing apoptosis of autoreactive lymphocytes and play an important role in inhibiting the pathogenesis of SLE.
However, there are still many problems in the traditional clinical application of As2O3, such as high toxicity, and low bioavailability, etc. At present, the clinically used preparation is through an arsenious acid injection made from As2O3. After intravenous administration, as elevated arsenic concentrates in plasma and rapidly diffuses into the surrounding tissue, side effects including but not limited to: gastrointestinal symptoms, peripheral neuritis, dry skin, pigmentation, even renal damage or ascites can occur in the patient. Since safe dose of As2O3 systemic administration is very limited and the difference between a safe dose and a toxic dose is infinitesimally small, which limits its application as a chemotherapeutic agent.
Therefore, when seeing the clinical value of As2O3 medicine, if we can improve the traditional preparation process, and adopt modern technology to prepare new As2O3 nanoparticles, thereby increasing the bioavailability, reducing drug dosage and toxicity, and improving efficacy, it will have important clinical significance.
The existing preparing process of nanoparticles preparation containing As2O3:
1. Zhou Jie et al (Chinese Journal of New Drugs 2005 14 (1) 54) disclosed a process for preparing arsenic trioxide-albumin microspheres through a method of emulsion-glutaraldehyde solidification; this method not only uses a large amount of organic solvent and oil, but also requires more chemical crosslinking agents-glutaraldehyde, the residual of which will bring some potential safety hazard to the application of preparations. 2. Chenhua Jiang (Second Military Medical University 2007.28 (6) 644) disclosed a process for preparing arsenic trioxide albumin microspheres by an emulsification-heat solidification method; 3. Yang Zhiwen, etc. (Traditional Chinese Medicine 2007 25 (8) 115) disclosed a process for preparing arsenic trioxide albumin microspheres by a emulsification-heat-stabilization method, which requires castor oil, cottonseed oil, and large amounts of organic solvent for removing the oily residue. The latter two methods, either an emulsion-glutaraldehyde solidification method or an emulsification—heat-stabilization method, have complicated technical processes and are unsuitable techniques for mass-production.
In the initial research phase of preparing arsenic compound-loaded nano-particles it was found, through many trials, that the particle size of nanoparticles prepared by a emulsion-heat-solidification method using castor oil could vary greatly, with a complicated technical process; and then it is switched to a desolvation-glutaraldehde chemical solidification method, but due to a large specific surface area of nanoparticles, the nanoparticles having not been solidified easily merge into big grains large clumps during stirring, which increases the likelihood of cross-linking between nanoparticles. The prepared particle will be too large, have a relatively short release time, contain residual glutaraldehyde chemical reagents, and require complicated technical processes, making it unviable for industrial production.
In summation, the prior art has complicated technical processes; hidden danger from residual toxic reagent glutaraldehyde; and a short release time, poor stability, poor storage stability, etc. There is an urgent need to develop a new process for preparing As2O3 loaded nanoparticles preparation.